The present invention relates to (E)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine of the formula [A]
which is a synthetic intermediate for pharmaceutically useful mequitazine having antihistaminic action and the like, and which has a purity of not less than 85 mol % (hereinafter to be also referred to as compound [A]) and a production method thereof. In addition, the present invention relates to a production method of a compound of the formula [I]
wherein X is a halogen atom, which is an intermediate for the above-mentioned compound [A], (hereinafter to be also referred to as compound [I]), and to a hydrate and a novel crystal of compound [III], which are used for the production of compound [I].
The mequitazine of the following formula 
is a pharmaceutically useful substance having various actions such as antihistaminic action, cholinergic action-inhibitory action, antiadrenergic action, neurosedative action, ataractic action, spasmolytic action and the like. Mequitazine can be produced by the following reaction 
werein R1 and R2 are the same or different and each is hydrogen atom, halogen atom, alkyl, alkoxy or alkylthio, in which 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is reduced in the presence of a reducing agent or hydrogenation catalyst to give mequitazine (JP-B-2835413).
According to this method, the reaction proceeds at a high temperature. Up-scaling, therefore, leads to the occurrence of thermal decomposition and elimination of hydrogen halide. This in turn causes degradation of the quality and yield of mequitazine, the need for column purification and hydrogenation, and the like. For use at an industrial level, therefore, an improvement is essential. When a boron compound is used as a reaction reagent, moreover, an adduct of the product and boron is generated, which requires addition of an acid (e.g., acetic acid) and heat treatment of the mixture.
Other production method of mequitazine may be the following series of reactions: 
wherein R1 and R2 are as defined above (JP-A-5-140157). According to this method, 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is subjected to elimination of hydrogen halide in an inert solvent in the presence of a base, such as hydroxide, hydride or alcholate of an alkali metal, to give three kinds of intermediates, which are hydrogenated without separation to produce mequitazine. In this method, hydrogenation is carried out using an expensive hydrogenation catalyst, such as palladium carbon, in the same amount as the intermediate, thereby resulting in higher production costs.
In view of such situation, there has been a demand for a method for industrial production of mequitazine at a high purity, a high yield and at a lower cost.
According to the present invention, it has been found with regard to the above-mentioned three kinds of intermediates (compound [Axe2x80x2], compound [Bxe2x80x2], compound [Cxe2x80x2]) as disclosed in JP-A-5-140157, that, of the compounds wherein R1 and R2 are hydrogen atoms [compound [A], (Z)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine (hereinafter to be also referred to as compound [B]) and 10-(1-azabicyclo[2.2.2]oct-2-en-3-ylmethyl)phenothiazine (hereinafter to be also referred to as compound [C]), respectively], compound [B] is hardly subject to hydrogenation, and that compound [C], which is most susceptible to hydrogenation among the three kinds of intermediates, suffers from lower purity and lower yield when reacted under the conditions that selectively afford this compound, that is, the reaction of 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine and alkali metal alcholate in an alcohol solvent, because 10-(3-alkoxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is by-produced. In addition, it has been found that compound [A] is susceptible to hydrogenation and that this compound is most suitable as a synthetic intermediate for mequitazine. In short, the present inventors have found that production of compound [A] at a high purity is most beneficial for the production of mequitazine.
Compound [I] is useful as a starting material for compound [A]. Compound [I] can be obtained by reacting 3-methylenequinuclidine oxide of the formula [II]
hereinafter to be also referred to as Compound [II], and an alkali metal salt of phenothiazine (JP-B-2835413). 3-Methylene-quinuclidine oxide to be used as a starting material can be produced by a known synthetic method (U.S. Pat. No. 3,725,410, U.S. Pat. No. 3,792,053, JP-A-61-280497, JP-A-2-62883) via dimsyl sodium. However, dimsyl sodium is unstable and dangerous (Anzen Kogaku (Safe Engineering) Vol. 23, No. 5, 269-274 (1984)).
In JP-A-61-280497, Example 1. (a)-(ii), teaches how to scale up the production of 3-methylenequinuclidine oxide. In this Example, a dispersion of toluene, 3-quinuclidinone, trimethyloxo-sulfonium iodide and sodium hydride in paraffin is charged and then dimethyl sulfoxide is added dropwise. According to this method, sodium hydride and trimethyloxosulfonium iodide are added in advance and dimethyl sulfoxide is subsequently added. As a result, dimethyl sulfoxide reacts with sodium hydride to form dimsyl sodium, and then dimsyl sodium reacts with trimethyloxosulfonium iodide to form dimethyloxosulfonium methylide as well as dimethyl sulfoxide. In other words, the addition of even a single drop of dimethyl sulfoxide in this method theoretically results in the completion of the reaction, because it generates dimethyl sulfoxide which automatically reacts successively with previously-added sodium hydride. Anzen Kogaku, ibid, teaches the instability of this reaction system by stating that a dimsyl sodium solution placed under adiabatic conditions at 55xc2x0 C. for 5 hr moves on to a runaway reaction. In fact, a reproductive testing of the method of JP-A-61-280497 in a reaction vessel of a 2000 L level ended up in carbonization of the contents due to a runaway reaction occurred therein. To conclude, this method allows reaction of dimsyl sodium immediately after formation thereof, but once dimethyl sulfoxide is added, the above-mentioned series of reactions occur, thereby producing dimethyl sulfoxide, and the newly-generated dimethyl sulfoxide causes another cycle of the above-mentioned reactions. This makes termination of the reaction difficult, and the reaction heat causes run away of the reaction due to the autoexothermicity of dimsyl sodium, to the degree that the reaction may induce an explosion. An enlarged reaction scale increases the risk of explosion.
In Example 1(II) of JP-A-61-280497, 3-quinuclidinone is reacted with dimethyloxosulfonium methylide, and the resulting reaction mixture of 3-methylenequinuclidine oxide is poured into water and subjected to extraction with chloroform for post-treatment. This method includes a loss in the amount of the final product, which loss becomes even greater by the concentration after extraction. 3-Methylenequinuclidine oxide isolated by the method disclosed in this publication and an alkali metal salt of phenothiazine were condensed to give 10-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine of the formula [III]
(hereinafter to be also referred to as Compound [III]) only at an unstable yield of 0-50%. This is because 3-methylene-quinuclidine oxide cannot be isolated at a constant percentage, the method includes a great loss as mentioned above, and because extraction solvent chloroform remains from isolation and forms carbene with the alkali metal, causing resinification. Consequently, the compound [III] cannot be obtained at a constantly high yield.
In Example 2 of JP-B-2835413, compound [III] was reacted with phosphorus oxychloride in monochlorobenzene at 110-120xc2x0 C. for 13 hr to give compound [I] at a yield of 44%. In this reaction, higher reaction temperatures result in greater amounts of resinified components, thereby degrading hue and yield, but lower reaction temperatures improve hue and yield to a greater degree. For a higher yield to be achieved, therefore, refluxing in a solvent having a lower boiling point, such as 1,2-dichloroethane (bp 83xc2x0 C.) and chloroform (bp 61xc2x0 C.), may be employed. On the contrary, however, the use of these solvents should be avoided in consideration of a possible influence on human body and the environment.
There has been a demand for an industrially safe method of producing compound [I] efficiently and at a constantly high yield from 3-quinuclidinone via compound [II] and compound [III].
It is therefore an object of the present invention to provide compound [A] having a high purity, and a production method of this compound. Another object of the present invention to provide an industrially safe method of producing compound [I] efficiently and at a constantly high yield from 3-quinuclidinone via compound [II] and compound [III]. It is a still yet object of the present invention to provide a hydrate and a novel crystal of compound [III].
Such objects can be achieved by the present invention described in the following.
According to the present invention, an alkali metal compound, dimethyl sulfoxide, trimethyloxosulfonium halide and 3-quinuclidinone or a salt thereof are added in a specific order to produce 3-methylenequinuclidine oxide from 3-quinuclidinone industrially safely even at an enlarged scale. To be specific, dimethyl sulfoxide, trimethyloxosulfonium halide and 3-quinuclidinone or a salt thereof are charged in advance, and then an alkali metal compound is added to inhibit generation of dimsyl sodium. Dimsyl sodium thus produced immediately reacts with trimethyloxosulfonium halide to produce dimethyloxosulfonium methylide and 3-methylenequinuclidine oxide. Inasmuch as trimethyloxosulfonium halide is added to the reaction system in advance, unstable dimsyl sodium regarded as risk-carrying can be used for the reaction immediately after formation, and by the successive addition of an alkali metal compound, dimsyl sodium can be inhibited from being generated, which in turn enables industrially safe production of 3-methylenequinuclidine oxide.
When 3-methylenequinuclidine oxide produced according to the above-mentioned method is directly reacted with an alkali metal salt of phenothiazine without treatment or isolation, namely, by carrying out from the generation of 3-methylenequinuclidine oxide to the generation of compound [III] in one pot, compound [III] can be obtained at a constantly high yield.
When compound [I] is obtained from compound [III], a by-produced acidic gas is removed to promote the reaction, whereby the reaction temperature can be lowered and the reaction time can be shortened. When compound [I] is obtained from compound [III], water is added to promote the reaction.
By the above steps, compound [I] can be produced industrially safely, efficiently and stably at a high yield from 3-quinuclidinone via compound [II] and compound [III].
When compound [I] is subjected to elimination of hydrogen halide in glyme in the presence of at least one kind of a base selected from the group consisting of potassium hydroxide and potassium alkoxide, compound [A] having a high purity of not less than 85 mol % can be produced.